This invention relates to improved pharmaceutical gel formulations for the topical delivery of drugs. In another aspect, this invention relates to pharmaceutical topical gel formulations containing 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.
Pharmaceutical gel and cream formulations for topical delivery of drugs are well known. However, many such formulations are not suitable for certain applications due to problems with, for example, insolubility and/or degradation of the drug in the formulation, physical instability of the formulation (separation of components, thickening, precipitation/agglomerization of active ingredient, and the like), and due to irritation of the skin or mucosa to which the formulation is applied. Also, depending on the purpose of the formulation, it may be desirable if the formulation avoids systemic delivery of the active ingredient, particularly where side effects may result from such systemic delivery.
U.S. Pat. No. 5,238,944 discloses a topical formulation of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine which is effective for the treatment of genital warts and other diseases. However, although useful for its intended purpose, this formulation is a cream, subject to potential separation problems, and includes isostearic acid which makes it painful if applied to open lesions such as occur in the case of herpes simplex virus infection.
The compound 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol disclosed in U.S. Pat. No. 5,389,640 is from the same chemical class of compounds as 1-isobutyl-1H-imidazo[4,5-c]quinolin4-amine, although having some significantly different chemical, physical, and biological properties. The compound has been shown to induce interferon and tumor necrosis factor in mice and rats following oral administration. The compound has also been shown to induce interferon-xcex1, tumor necrosis factor, interleukin-1xcex1, interleukin-1xcex2, interleukin-6 and interleukin-8 in cultures of human peripheral blood mononuclear cells. The compound has also shown antiviral activity against herpes simplex virus-challenged guinea pigs when administered subcutaneously, dermally or intravaginally 24 hours before infection.
However, systemic administration of 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol may also be associated with certain side effects, including fever, malaise, headache, nausea and vomiting. Non-systemic topical cytokine induction would thus have the advantage of avoiding the side effects associated with the systemic induction of these ctyokines.
Accordingly, it is one object of the present to provide a highly stable pharmaceutical gel formulation that is suitable for topical application to the skin and/or mucosa.
A related object is to provide a gel formulation that is suitable for application to skin and/or mucosal lesions.
Another object is to provide a gel formulation in which 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol is soluble and does not substantially degrade during storage.
Yet another object is to provide a topical gel formulation for the topical delivery of 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol which does not deliver undue amounts of the active compound systemically.
These objects, as well as others that will become apparent upon reference to the following description, are provided by pharmaceutical gel formulations including a drug, colloidal silicon dioxide, triacetin and, preferably, propylene glycol. The drug is preferably 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, which has been found to be sufficiently soluble and chemically stable in gel formulations of the present invention. Moreover, it has been found that gel formulations of the present invention, unlike certain other gel formulations, provide excellent topical delivery of the drug while substantially avoiding unwanted systemic delivery (thereby avoiding side effects).
As noted, the gel formulations of the invention preferably include propylene glycol. One reason is because it appears, surprisingly, that inclusion of propylene glycol thickens the gel formulations and that the integrity of the resulting gel is maintained at body temperature. It should be noted, however, that gel formulations without propylene glycol, but including 4-amino-2-ethoxymethyl-xcex1,xcex1-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, colloidal silicon dioxide, and triacetin have been found to be suitable, although less preferred.
The present invention also provides a method of inducing cytokines, such as interferon and tumor necrosis factor, locally in the skin or mucous membranes of a mammal, comprising placing on the skin or mucous membranes of a mammal an amount of a formulation as described above effective to induce cytokines. The formulations of the present invention are also well-suited for treatment of diseases by application of the formulation to skin and/or mucosal lesions because the gel formulations do not need to include irritating components.